The accessory protein HIV-Nef plays an important role in the regulation of HIV pathogenesis. Recently we and others have shown that Nef is associated with the host protein kinase known as Nef Associated kinase (NAK). Recruitment of NAK by Nef is an important step for HIV production. NAK inhibitors will introduce a novel class of anti-HIV drugs that will target the host protein rather than viral proteins. To identify NAK, we will purify NAK from T Jurkat cells stably expressing Nef and will use the sequence information to obtain the full length DNA. Our preliminary results suggest that NAK is co-purified with Pak1 and Nef interacts with Pak1 in-vitro and in-vivo. We will further characterize the Pak1 and Nef interaction and will establish if NAK is identical to Pak1. We will make recombinant NAK to study the biochemical events leading to NAK activation and will test the effect of NAK mutants on HIV production. This approach may lead us to the discovery of anti-HIV drugs that will maintain efficacy in a virus that exhibits a high frequency of mutations. PROPOSED COMMERCIAL APPLICATIONS: We previously have shown that the association of HIV Nef with the host protein NAK is essential for HIV replication. Our preliminary results indicate that NAK is identical to known kinase Pak1. The development of a NAK specific inhibitor will allow us to identify a novel class of anti-HIV agents. Our research and development will introduce a novel approach in the development of anti viral agents and will expand our understanding of the mechanism of HIV pathogenesis.